U.S. patent number 7,279,583 [Application Number 10/582,283] was granted by the patent office on 2007-10-09 for process for the synthesis of perindopril and pharmaceutically acceptable salts thereof.
This patent grant is currently assigned to Les Laboratoires Servier. Invention is credited to Thierry Dubuffet, Jean-Pierre Lecouve.
United States Patent |
7,279,583 |
Dubuffet , et al. |
October 9, 2007 |
Process for the synthesis of perindopril and pharmaceutically
acceptable salts thereof
Abstract
Process for the industrial synthesis of perindopril of formula
(I): ##STR00001## and pharmaceutically acceptable salts
thereof.
Inventors: |
Dubuffet; Thierry (Autretot,
FR), Lecouve; Jean-Pierre (Le Havre, FR) |
Assignee: |
Les Laboratoires Servier
(Courbevoie Cedex, FR)
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Family
ID: |
32116381 |
Appl.
No.: |
10/582,283 |
Filed: |
December 9, 2004 |
PCT
Filed: |
December 09, 2004 |
PCT No.: |
PCT/FR2004/003166 |
371(c)(1),(2),(4) Date: |
June 09, 2006 |
PCT
Pub. No.: |
WO2005/066198 |
PCT
Pub. Date: |
July 21, 2005 |
Prior Publication Data
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Document
Identifier |
Publication Date |
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US 20070093663 A1 |
Apr 26, 2007 |
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Foreign Application Priority Data
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Dec 10, 2003 [EP] |
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03293084 |
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Current U.S.
Class: |
548/452 |
Current CPC
Class: |
C07K
5/06026 (20130101) |
Current International
Class: |
C07D
209/12 (20060101) |
Field of
Search: |
;548/452 |
Foreign Patent Documents
Other References
Li, Peng, et al., "New and highly efficient immonium-type peptide
coupling reagents: syntheisi, mechanism, and application"
TETRAHEDRON, vol. 56, No. 26, p. 4437-4445, 2000. cited by other
.
Li, Peng, et al., "BOMI--a novel peptide coupling reagent"
Tetrahedron Letters, vol. 40, No. 18, p. 3605-3608, 1999. cited by
other .
Li, Peng, et al., "The development of highly efficient anium-type
peptide coupling reagents based upon rational molecular design"
Journal of Peptide Research, vol. 58, No. 2, p. 129-139, 2001.
cited by other .
Coste, Jacques, et al. "Oxybenzotriazole free peptide coupling
reagents for N-methylate amino acids" Tetrahedron Letters, vol. 32,
No. 17, p. 1967-1970, 1991. cited by other .
Carpino, Louis, et al., "Effect of Tertiary basis on
)-benzotriazolyluronium salt-induced peptide segment coupling"
Journal of Organic Chemistry, vol. 59, No. 4, p. 695-698, 1994.
cited by other .
Chen, Shaoqing, et al, "A coupling reagent for peptide synthesis.
Benzotriazolyloxybis(pyrrolidine)carbonium
hexafluorophosphate(BBC)" Tetrahedron Letters, vol. 33, No. 5, p.
647-650, 1992. cited by other .
International Search Report for PCT/FR2004/003166--May 3, 2005.
cited by other .
European Search Report for EP 03293084--Mar. 18, 2004. cited by
other.
|
Primary Examiner: Saeed; Kamal A.
Assistant Examiner: Barker; Michael P.
Attorney, Agent or Firm: Hueschen and Sage
Claims
What is claimed is:
1. A process for the industrial synthesis of perindopril of formula
(I) ##STR00005## and pharmaceutically acceptable salts thereof,
wherein a benzyl ester of formula (IIa) or (IIb): ##STR00006## or
an addition salt of the ester of formula (IIa) or (IIb) with a
mineral acid or organic acid, is reacted with a compound of formula
(III): ##STR00007## in the presence of a coupling agent selected
from: 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide
hydrochloride/1-hydroxybenzotriazole and propanephosphonic
anhydride, optionally in the presence of a base, to yield, after
catalytic hydrogenation in the presence of palladium, perindopril
of formula (I), which is converted, if desired, into a
pharmaceutically acceptable salt.
2. The process of claim 1 for the synthesis of perindopril in the
form of its tert-butylamine salt.
3. The process of claim 1, wherein the compound of formula (IIa) is
used as starting material.
4. The process of claim 1, wherein the compound of formula (IIb) is
used as starting material.
5. The process of claim 3, wherein the hydrogenation reaction is
carried out under a hydrogen pressure of less than 10 bars.
6. The process of claim 4, wherein the hydrogenation reaction is
carried out under a hydrogen pressure of from 10 to 35 bars.
Description
The present invention relates to a process for the synthesis of
perindopril of formula (I):
##STR00002## and pharmaceutically acceptable salts thereof.
Perindopril and its pharmaceutically acceptable salts, and more
especially its tert-butylamine salt, have valuable pharmacological
properties.
Their principal property is that of inhibiting angiotensin I
converting enzyme (or kininase II), which allows, on the one hand,
prevention of the conversion of the decapeptide angiotensin I to
the octapeptide angiotensin II (a vasoconstrictor) and, on the
other hand, prevention of the degradation of bradykinin (a
vasodilator) to an inactive peptide.
Those two actions contribute to the beneficial effects of
perindopril in cardiovascular diseases, more especially in arterial
hypertension and heart failure.
Perindopril, its preparation and its use in therapeutics have been
described in European patent specification EP 0 049 658.
In view of the pharmaceutical value of this compound, it has been
important to be able to obtain it by an effective synthesis
process, readily transposable to an industrial scale, that leads to
perindopril in a good yield and, especially, with excellent
purity.
Patent specification EP 0 308 341 describes the industrial
synthesis of perindopril by the coupling of
(2S,3aS,7aS)-octahydroindole-2-carboxylic acid benzyl ester with
N-[(S)-1-carboxybutyl]-(S)-alanine ethyl ester in the presence of
dicyclohexylcarbodiimide, followed by deprotection of the
carboxylic group of the heterocycle by catalytic hydrogenation.
That process has disadvantages related to use of the
dicyclohexylcarbodiimide.
The Applicant has developed a process for the synthesis of
perindopril that uses other coupling agents.
More specifically, the present invention relates to a process for
the synthesis of perindopril, which process is characterised in
that the benzyl ester of formula (IIa) or (IIb):
##STR00003## or an addition salt of the ester of formula (IIa) or
(IIb) with a mineral acid or organic acid is reacted with the
compound of formula (III):
##STR00004## in the presence of a coupling agent selected from the
following reagents and pairs of reagents:
(1,3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride,
(1,3-dimethylaminopropyl)-3-ethyl-carbodiimide
hydrochloride/1-hydroxybenzotriazole,
(1,3-dimethylaminopropyl)-3-ethyl-carbodiimide
hydrochloride/1-hydroxy-7-azabenzo-triazole,
(1,3-dimethylaminopropyl)-3-ethyl-carbodiimide
hydrochloride/N-hydroxysuccinimide,
(1,3-dimethylaminopropyl)-3-ethyl-carbodiimide
hydrochloride/3-hydroxy-3,4-dihydro-4-oxo-1,2,3-benzotriazine,
(1,3-dimethylaminopropyl)-3-ethyl-carbodiimide
hydrochloride/N-hydroxyphthalimide,
dicyclohexylcarbodiimide/1-hydroxy-7-azabenzotriazole,
dicyclohexylcarbodiimide/N-hydroxysuccinimide,
dicyclohexylcarbodiimide/3-hydroxy-3,4-dihydro-4-oxo-1,2,3-benzotriazine,
dicyclohexylcarbodiimide/N-hydroxyphthalimide,
O-(benzotriazol-1-yl)-1,1,3,3-tetramethyluronium
hexafluorophosphate,
O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium
hexafluorophosphate,
O-(benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate,
benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate,
benzotriazol-1-yl-oxy-tris(dimethylamino)phosphonium
hexafluorophosphate,
O-(benzotriazol-1-yl)-1,1,3,3-bis(tetramethylene)uronium
hexafluorophosphate,
O-(benzotriazol-1-yl)-1,1,3,3-bis(pentamethylene)uronium
hexafluorophosphate, chloro-tripyrrolidinophosphonium
hexafluorophosphate,
chloro-1,1,3,3-bis(tetramethylene)formamidinium
hexafluorophosphate,
chloro-1,1,3,3-bis(pentamethylene)formamidinium
hexafluorophosphate,
N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline,
O-[(ethoxycarbonyl)-cyanomethyleneamino]-1,1,3,3-tetramethyluronium
tetrafluoroborate,
O-(3,4-dihydro-4-oxo-1,2,3-benzotriazin-3-yl)-1,1,3,3-tetramethyluronium
tetrafluoroborate,
O-(3,4-dihydro-4-oxo-1,2,3-benzotriazin-3-yl)-1,1,3,3-tetramethyluronium
tetrafluoroborate/1-hydroxybenzotriazole,
O-(3,4-dihydro-4-oxo-1,2,3-benzotriazin-3-yl)-1,1,3,3-tetramethyluronium
tetrafluoroborate/N-methylmorpholine,
O-(3,4-dihydro-4-oxo-1,2,3-benzotriazin-3-yl)-1,1,3,3-tetramethyluronium
tetrafluoroborate/collidine,
O-(1,2-dihydro-2-oxo-1-pyridyl)-1,1,3,3-tetramethyluronium
tetrafluoroborate,
O-(1,2-dihydro-2-oxo-1-pyridyl)-1,1,3,3-tetramethyluronium
tetrafluoroborate/1-hydroxybenzotriazole,
O-(1,2-dihydro-2-oxo-1-pyridyl)-1,1,3,3-bis(tetramethylene)uronium
hexafluorophosphate,
O-(1,2-dihydro-2-oxo-1-pyridyl)-1,1,3,3-bis(tetramethylene)uronium
hexafluoro-phosphate/1-hydroxy-benzotriazole,
O-(N-succinimidyl)-1,1,3,3-tetramethyluronium tetrafluoroborate,
O-(N-succinimidyl)-1,1,3,3-bis(tetramethylene)uronium
tetrafluoroborate,
O-(N-succinimidyl)-1,1,3,3-bis(tetramethylene)uronium
tetrafluoroborate/1-hydroxy-benzotriazole,
O-(5-norbornene-2,3-dicarboximido)-1,1,3,3-tetramethyluronium
tetrafluoroborate, propanephosphonic anhydride,
N-hydroxy-5-norbornene-2,3-dicarboxylic acid imide, and
N-hydroxy-1,2-dihydro-2-oxo-pyridine, optionally in the presence of
a base, to yield, after catalytic hydrogenation in the presence of
palladium, perindopril of formula (I), which is converted, if
desired, into a pharmaceutically acceptable salt such as the
tert-butylamine salt.
When the compound of formula (IIa) is used as starting material,
the catalytic hydrogenation is preferably carried out under a
hydrogen pressure of less than 10 bars.
When the compound of formula (IIb) is used as starting material,
the catalytic hydrogenation is preferably carried out under a
hydrogen pressure of from 10 to 35 bars.
The example hereinbelow illustrates the invention.
EXAMPLE 1
Benzyl
(2S,3aS,7aS)-1-{((2S)-2-[(1S)-1-(ethoxycarbonyl)-butylamino]-propio-
nyl}-octahydro-1H-indole-2-carboxylate
200 g of (2S,3aS,7aS)-octahydroindole-2-carboxylic acid benzyl
ester para-toluene-sulphonate, 65 ml of triethylamine and 1 litre
of ethyl acetate are introduced into a stirred reactor, followed,
after stirring for 10 minutes at ambient temperature, by 100 g of
N-[(S)-ethoxycarbonyl-1-butyl]-(S)-alanine and 175 g of
O-(benzotriazol-1-yl)-1,1,3,3-bis(tetra-methylene)uronium
hexafluorophosphate. The heterogeneous mixture is then heated at
30.degree. C. for 3 hours whilst stirring well and is then cooled
to 0.degree. C. and filtered.
The filtrate is then washed and subsequently evaporated to dryness
to yield the expected product.
EXAMPLE 2
(2S,3aS,7aS)-1-{(2S)-2-[(1S)-1-(Ethoxycarbonyl)-butylamino]-propionyl}-oct-
ahydro-1H-indole-2-carboxylic acid
The residue obtained in the previous step (200 g) is dissolved in
200 ml of methyl-cyclohexane and transferred to a hydrogenator; 26
g of 5% palladium-on-carbon suspended in 80 ml of methylcyclohexane
are then added, followed by 640 ml of water.
The mixture is then hydrogenated under a pressure of 0.5 bar at a
temperature of from 15 to 30.degree. C., until the theoretical
amount of hydrogen has been absorbed.
After filtering off the catalyst, the aqueous phase of the filtrate
is washed with methylcyclohexane and then lyophilised to yield the
expected product in a yield of 94%.
EXAMPLE 3
(2S,3aS,7aS)-1-{(2S)-2-[(1S)-(Ethoxycarbonyl)-butylamino]-propionyl}-octah-
ydro-1H-indole-2-carboxylic acid tert-butylamine salt
The lyophilisate obtained in the previous step (200 g) is dissolved
in 2.8 litres of ethyl acetate, and then 44 g of tert-butylamine
and 400 ml of ethyl acetate are added.
The suspension obtained is then refluxed until dissolution is
complete; then the solution obtained is filtered whilst hot and
cooled to a temperature of 15-20.degree. C., with stirring.
The precipitate obtained is then filtered off, made into a paste
again using ethyl acetate, dried and then ground to yield the
expected product in a yield of 95%.
* * * * *